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Executive Publishers

Megha Agrawal, PhD Shyamasri Biswas, PhD

(Biotechnology) (Biotechnology)

Publisher and Editor Publisher and Editor

Expertise: Expertise:

Neuroscience, Stroke, Pharmacology, Structural Biology, Enzyme Technology, Toxicology, Microbiology and and Protein Crystallography Molecular Biology

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ISSN 2689-0852 One stop shop for all things biotech

Biotechnology Kiosk ISSN 2689-0852 Volume 1, Issue 6 Page 1

From the Publisher’s Desk

Welcome to Biotechnology Kiosk!

We launched Biotechnology Kiosk (BK) in

June, exactly seven months ago. With the 7th

issue of Biotechnology Kiosk, we are now

concluding the year 2019, and look forward

to continue serving our readers in 2020 and

beyond. As usual, the regular features

include high-end editorials by experts,

biotechnology advances around the world

and industry news from pharma and biotech

sectors.

We are proud to present some metrics

to have insights into the accomplishments of

BK so far. Since its launch, we have

published over 25 scholarly editorials by

leading experts in a broad range of areas in

biotechnology. Numerous latest exciting

discoveries in modern biotechnology R&D in

a vast array of cutting edge fields have also

been covered by us in the Editor’s Picks

section of BK. We are proud and honored to

have as many as seven distinguished

international experts on our editorial board as

advisors of BK. In addition, BK has an ISSN

now and will soon be a member of the digital

object identifier (DOI) worldwide network for

cross referencing of the published materials

in BK. Our plans for BK for the New Year

include partly transforming the magazine into

an open access magazine that will publish


peer reviewed articles in biotechnology in

special editions while keeping the trade

aspects and nature of BK.

We do hope that you will enjoy reading

this issue of Biotechnology Kiosk. Please do

write to us with your comments and

feedback. Your suggestions are always

appreciated.

We take this opportunity to wish our readers

Happy Holidays!

Dr. Megha Agrawal and Dr. Shyamasri

Biswas

Executive Publishers and Editors


Contents

VOLUME 1, ISSUE 7 DECEMBER 2019

COLUMNS

BIO-NANOTECHNOLOGY ……………..…...……………………………………………………......5

Nature’s very own nanoparticles are the new gene delivery agents: The promising role of Exosomes in gene therapy

SYNTHETIC BIOTECHNOLOGY…………………...……………………………….………...……10

Advances in Synthetic Biology to Manipulate Living Systems

NEUROPROSTHESES…………………………………...…………………….…………….……...15 Intra Spinal Micro-Stimulation Implant Technology Shows Promise for Clinical Implementation

REGENERATIVE MEDICINE.............................................................................................…...19 The Emerging Potentials of Exosome-Based Drug Delivery

BIOTECH R&D AND INNOVATION NEWS…………………….……………………………….…24

EDITOR’S PICKS: BIOTECHNOLOGY ADVANCES AROUND THE WORLD

Marine Biotechnology ………………………………………………………………………………25

Environmental Biotechnology ………………………………………………………………...…..25

Virology ……………………………….……………………………………………………………….26

Tropical Medicine …………....………………………………………………………………………27

Alternative Medicine ………………………………………………………………….....................27


BIOTECHNOLOGY AND PHARMA INDUSTRY ROUNDUP……………………………………29

Positive data on trastuzumab deruxtecan….....…………………………………………..…….29

Pembrolizumab promise in lung cancer ………………….……………………………………..29

Alvogen to acquire Gralise® (gabapentin) ……………..……………………………………….29

Eleven biopharma filed for bankruptcy in 2019………………..……………………………...29

Sanofi plans for $2.2B in cost cutting …..……………………...………………………..………30

The British pharma AstraZeneca is growing…………………..………………………………..30

Merck acquisition of biotech firm ArQule ……….………………….………………………….30

Bioncotech Therapeutics enters into a Phase II clinical trial..…………………….…….......30

Pierre Fabre to amend agreement with Puma Biotechnology…….…………………………30

ADVERTISING INFORMATION……………………………………………………………………..31

(a) WEB BANNER AND ADVERTISEMENT RATES

(b) GENERAL AD RATES FOR THE MAGAZINE


Bio-nanotechnology

By Shripriya Singh, PhD Contributing Editor

Nature’s very own nanoparticles are the new gene delivery

agents: The promising role of Exosomes in gene therapy

Evolving of the field of therapeutics:

From organ therapeutics to molecular

therapeutics

The word research spells curiosity, intrigue,

and uncertainty and the term medicine spells

treatment, healing and cure. Whereas, when

the two come together in form of medical

research, the term spells change, hope and

good health. Research potentially comprises

two main phases, first in which we develop an

understanding of the subject and delve at the

grass root level of the existing problems and

the second phase of research deals with

solutions and tries to provide answers for the

rediscovered problems. In the present times

we have successfully transitioned to the

second phase where researchers across the

globe are focusing on answers and solutions.

This aspect of research has brought a

tremendous change in the field of medicine

where diseases no longer intrigue doctors

and practitioners; instead they are tackled

with precision and accuracy. Medical

advancements have led us systematically

from organ therapeutics to organellar

therapeutics to cellular therapeutics and

finally to molecular therapeutics. Thereby, we

are gradually heading towards an era of

precision medicine where the focus is on

molecular targets such as specific genes.

Gene therapy, genetic engineering and

nucleic acid based therapeutics have shown

immense potential and hold a promise to

abrogate diseased states in their infancy.

The manipulation of genetic

machinery of an organism is one of the most

interesting aspects of biotechnology and has

opened endless avenues for researchers.

However, the delivery of any foreign particle

such as a drug, a xenobiotic, an antigen or a

fragment of nucleic acid is the trickiest part of

the job. Every living organism has an efficient

natural defense system via which it restricts

and resists the entry of any foreign

substance. This efficient defense mechanism

which is popularly known as the ‘immune

system’ is by far the biggest challenge in the

field of medicine. In case of stem cell based

therapeutics, regenerative medicine, organ

transplantation and even gene therapy, this


major hurdle has to be overcome and

resolved. Thus the approach is to use the

patients’ own tissues and cells for any further

treatment.

Bio nanotechnology offers hope in gene

therapy

In one of our previous articles we had

discussed about nanochips and tissue nano-

transfection (TNT), an innovative technology

which allows body to regenerate any type of

cell through genetic reprogramming. As

mentioned earlier the nanochip is a simple

yet unique miniscule device designed around

the novel concept of tissue nano-transfection.

TNT is an electroporation based technique

that facilitates the direct delivery of

reprogramming factors (DNA) into the cytosol

via the application of a focused and highly

intense electric field through arrayed

nanochannels. The electric field benignly

nanoporates the cell membrane and the

reprogramming factors are

electrophoretically driven in (1). Keeping in

pace with this advancing technology we take

the story forward and our current article is

focused on exosome mediated gene delivery

via cellular nanoporation (2).

What is exosome mediated gene delivery

- the concept and details of the

technology

Exosomes are membrane bound

extracellular vesicles (EVs) secreted

routinely by all cells of the body. They are

considered the smallest organelles possibly

present inside a cell and are capable of

expelling metabolic byproducts and help in

protein clearance. Exosomes are also

routinely present in biological fluids such as

blood, plasma and even the secretome of

cells cultured in-vitro. Their nano scale size

(40–150 nm in diameter) and abundant

presence have compelled biologists to

consider them as potent tools of

biotechnological use. Gene therapy and

nucleic acid based therapeutics hold great

promise for treating multiple human

diseases. However, the inefficient delivery of

negatively charged and relatively large

molecules into cells and tissues of interest

has been a major drawback of the process.

Several in vivo gene delivery methods and

techniques have been developed and

improved over the past years to accomplish

precision and efficiency. These techniques

comprise synthetic nanocarriers such as

polymeric and liposomal nanoparticles and

viral vectors. However, these strategies have

suffered on grounds of immunogenicity,

toxicity and manufacturing costs. The quality

control of manufactured products and the

high cost incurred have added to the burden

further. However, the biggest drawback of the

existing techniques has been their inability to

deliver the cargo across specific

physiological barriers such as the blood-brain

barrier (3).

Recently exosomes have emerged as

potential carriers for nucleic-acid-based

therapeutics (4) and the method takes

advantage of these fluid-filled sacs that cells

release as a way to communicate with other

cells. The scientists used the technique of

cellular nanoporation in which they placed

around one million donated cells (such as

mesenchymal cells collected from human fat)

on a nano-engineered silicon chip and used

an electrical stimulus to inject synthetic DNA

into the donor cells. As a consequence of this

DNA force-feeding the cells are compelled to


eject the unwanted substance as part of DNA

transcribed messenger RNA and induced to

repair the holes that have been induced in

their membranes. This serves two main

purposes, first the leakage to the cell

membrane is fixed and secondly the garbage

is dumped outside the cell. In this case as

mentioned by the authors the garbage bag is

the exosome which carriers the drug or the

nucleic acid fragment of interest. The

electrical stimulation had an additional effect

of a thousand-fold increase of therapeutic

genes in a large number of exosomes which

were released by the cells. This is a clear sign

that the technology is scalable to produce

enough nanoparticles required for human

use. Figure 1 depicts the proposed

mechanism of CNP.

Figure 1: Schematic representation of the proposed mechanism for Cellular Nanoporation (CNP)

triggering of exosome release in CNP-transfected cells. [Source: Nature Biomedical

Engineering 2019.]

The knowledge of the exact molecular target

and the exact gene responsible are crucial for

the success of gene therapies. To test the

efficacy of the above mentioned technique

scientists chose to test the results on glioma

brain tumors of mice by delivering a cancer-

suppressor gene called PTEN. Mutations in

the PTEN gene interfere with the suppression

role and thus allow cancer cells to proliferate

and grow unchecked. Gliomas represent


about eighty percent of malignant brain

tumors in humans and thus were a target of

interest. The results clearly showed that

labeled exosomes carrying the gene of

interest not only travelled to the brain tumors

accurately but slowed their growth as

compared to the test substances used as

control. Further these gene carrying

exosomes restored the tumor suppressor

function, inhibited the growth and spread of

malignant tissues and increased overall

survival. Figure 2 depicts the overall

technique and its application in mice gliomas.

Figure 2: Diagrammatic representation of CNP-generated exosomes for targeted gene delivery.

Left: the CNP system comprises a nanochannel array (red rectangles). Plasmid DNA added to

the buffer enters attached cells via nanochannels under transient electrical pulses. Attached

cells subsequently release large quantities of exosomes containing transcribed mRNA that can

be collected for tumor-targeted delivery through the blood–brain barrier (BBB) or blood–brain

tumor barrier (BBTB) (right). [Source: Nature Biomedical Engineering 2019.]

The current and future aspects of the

exosome based nano-carriers

Exosomes are superior to any artificially

made nano-carriers as they are non toxic,

biocompatible and do not evoke an immune

response in the patients. They express

transmembrane and membrane-anchored

proteins which prolong their circulation in

blood and help them in transport. These

proteins further facilitate the cellular uptake of

encapsulated exosomal contents and helps

in tissue-directed delivery of genes. The only

drawback was the large scale production and

purification of exosomes which have been

overcome by the technique of cellular

nanoporation (CNP) discussed in this article.

Thus CNP helps in injecting of the nucleic

acid (gene of interest) into the cell and

simultaneously produces a large number of

exosomes (50 fold more than normal)


carrying the same genetic transcript. The

biggest advantage of these exosome based

carrier is that they can efficiently cross the

blood brain barrier and thus will provide

endless opportunities for treating

neurodegenerative diseases such as

Alzheimer's and Parkinson's disease. Since

the study was published in December the

authors have fondly termed their innovative

method as a small Christmas gift for the

medical and research fraternity. The

exosomes are like nature induced parcels

that will carry the healing gift (gene or drug)

inside and will efficiently deliver to the

molecular target of interest. They are being

referred to as “Mother Nature-induced

therapeutic nanoparticles”. A small

modification in tissue nanotransfection (TNT)

has led us towards cellular nanoporation.

This small innovative technology has once

again proven how smoothly we are

progressing towards achieving goals that

seemed miraculous a while ago. This

technique holds immense potential as it is a

simple, efficient and cost friendly method via

which we can deliver drugs of interest and

genes required for treating and repairing

medical issues at a very nascent stage. This

is a new gene therapy technique where the

body’s own natural process has been tapped

and manipulated to serve as a drug delivery

system. The breakthrough research has

transformed human cells into mass

producers of miniscule nanoparticles full of

genetic material that could possibly cure or

even reverse disease conditions.

References

1. Gallego-Perez D, et al. (2017) Topical

tissue nano-transfection mediates non-

viral stroma reprogramming and rescue.

Nature nanotechnology 12(10):974.

2. Yang Z, et al. (2019) Large-scale

generation of functional mRNA-

encapsulating exosomes via cellular

nanoporation. Nature Biomedical

Engineering:1-15.

3. Singh A, et al. (2016) Multifunctional

photonics nanoparticles for crossing the

blood–brain barrier and effecting optically

trackable brain theranostics. Advanced

functional materials 26(39):7057-7066.

4. Andaloussi SE, Mäger I, Breakefield XO,

& Wood MJ (2013) Extracellular vesicles:

biology and emerging therapeutic

opportunities. Nature reviews Drug

discovery 12(5):347-357.


Synthetic Biotechnology

By Peeyush Prasad, MSc Contributing Editor

Advances in Synthetic Biology to Manipulate Living Systems

The Significance of Synthetic Biology in

Living Systems

Imagine a future where you can create

anything by manipulating living system and

we will reach up to the idea of genetically

modified organism. But how about creating

new life forms for getting desired things such

as life-saving cancer drugs, fuels, sensors,

diagnostics, enzymes, storing data and

electricity? Here, we are talking about

synthetic life which started from few people’s

bold attempt to understand what life is at its

very basic level. Discovery of DNA to

discovery of tools to manipulate DNA, we

have come very far where we can precisely

alter gene by using technology such as

CRISPR-Cas9. Idea of synthetic life became

reality when Craig Venter reported the

design, synthesis and assembly of the 1.08-

mega-base pair Mycoplasma mycoides

JCVI-syn1.0 genome. Chemically

synthesized genome was inserted into the M.

capricolum and new M. mycoides was

created. They called it synthetic cell as

progeny cells contained the new set of

proteins coded from transplanted genome

[1].

Further, several researches came into

light that tried to create or manipulate the

organism fundamentally for getting desired

products. Synthetic life is usually designed by

forward-engineering approach [2] that usually

aims to create new molecular function. At the

same time there is lack of consensus on what

should be called as synthetic life. Is the

synthetic life a total new creation of organism

from scratch or is it just the alteration in the

organism for finding new molecular function

such as production of artemisinin in yeast

cells. In one of the research, team of

scientists has introduced the gene which

converts the FPP into artemisinic acid and

inhibited the gene which converts the FPP in

yeast into ergosterol for producing

artemisinin. Artemisinin is produced by plant

A. annua (sweet wormwood) [3, 4]. Artificial

gene circuit can be used for finding cure for

cancer such as development of gene circuits

based on adaptive programming. Three

components: a sensor for detecting inputs, a

processor and an actuator which produces


responses are integrated in artificial multi-

gene circuits [5]. These circuits are based on

transcriptional networks and regulators

(Table 1).

Company Function Link

Synthetic Genomics

Working on algal proteins and oil,

microbial therapeutics platform

(CmaxTM), self replicating RNA

medicine, growing organs from

engineered pig cells and

bacteriophage platform for

countering bacterial resistance.

Company has developed the first

automated DNA printer (BioXp).

https://syntheticgenomics.com/

Arzeda

A protein design company which

builds its molecules from scratch

for performing new function by

using deep learning. Working in

the field of agriculture,

pharmaceuticals and diagnostics,

functionalized sweetners and

ingredients and advanced

chemicals and materials.

https://www.arzeda.com/

Twist Bioscience

Working in the field of medicine,

agriculture, industrial chemicals

and data storage. Created an

innovative silicon-based DNA

synthesis platform.

https://www.twistbioscience.com

/

Synbicite

Working in the field of medicine,

agriculture and biofuels along

with others. Provide services such

as DNA synthesis, microfluidics,

genome editing (CRISPR-Cas9)

etc.

http://www.synbicite.com/

Table 1: Companies working in the field of synthetic biology.

Reprogramming of Cells and Bacteria: An

Example of Synthetic Biology in Cancer

Cells

Cancer cells have multiple signatures and it

is important that immune cells must be able

to recognize the plethora of variations in the

cancer cells for counter measures.

Reprogramming of T-cells can be done so

that it can recognize the different combination

of antigens. For example, use of Synthetic

Notch (SynNotch) receptor T cell AND gate

[6]. It has been observed that several

bacteria specifically accumulate around the

tumor therefore these bacteria can be

manipulated for delivering specific

therapeutics at tumor site [7]. In another

https://syntheticgenomics.com/

https://www.arzeda.com/

https://www.twistbioscience.com/

https://www.twistbioscience.com/

http://www.synbicite.com/


study, researchers have developed the

artificial version of E. coli (Syn61) present in

stomach which can be used for the synthesis

of drugs, catalysts, enzymes etc. In this case

4 million genetic code of Syn61 is

synthesized from scratch [8]. Creating

eukaryotic organism is another challenge due

to complexity of its component. In one of

initiative, group of scientists are trying to

synthesize the yeast (SC 2.0) genome. The

study will provide the information about

genome organization, gene content and role

of RNA in yeast biology [9]. Other than

manipulating the molecular function inside

cells, researchers is trying to create the cells

from scratch. Synthetic cell is consist of

micro-compartments encapsulating

biochemical molecules such as DNA, RNA,

proteins, ribosomes, enzymes, ATP etc.

These cells closely mimic the natural cells

[10]. Figure 1 describes the direction of

research currently going on in synthetic cell

research.

Figure 1. Schematic drawings representing some of the current directions in SC research. (a)

Functionalization of the SC membrane-by-membrane proteins or similar components. Note that

orientation, shown in (b), becomes an important issue when dealing with vectorial systems as

membrane proteins. (c) The nested multicompartment system, or multivesicular vesicle, also

known as “vesosome”, is a SC design that allow exploitation of compartmentation, hierarchical

levels, chemical gradients across the membranes. (d,e) Assemblies of SCs in two and three

dimensions. (f) SCs embedded in biocompatible gel. (g,h) Molecular communication between

SCs or between SCs and biological [Source: Stano P. Life. 2019].

Products Source Company

Synthetic rubber (BioIsoprene™) Bacterial fermentation DuPont and Goodyear

Soybean tire Soybean oil Goodyear

Acrylic Genetically engineered microbe OPX Biotechnologies

Biofuels Synthetic algae Synthetic Genomics

Table 2: Important products from synthetic biology.


The Future Prospects of Synthetic

Biology

Development of new technology

brings the question of ethics and safety.

Autodesk which works in the field of software

built its own virus (Phi-X174 bacteriophage).

Genome of this virus consisted of 5,386 base

pairs of nucleotides. This virus could infect

the E. coli but was not harmful for human [11].

But this kind of research often leaves us with

the question of how far man can go into his

endeavor to intervene with nature. At what

point we need to stop and what are the long

term consequences of these researches?

Life which we see today is outcome of

millions of years of evolutionary process

where errors often get ample time to adjust in

the evolving system but suddenly introducing

new organism can be a shock to the system.

We have seen how genetically modified crop

not only kills the pest against which it is

developed but it also harms the other

organisms. We are already struggling with

multi antibiotic resistant infectious organisms

and we have not yet found the drugs for many

viral disease. Synthetic life has not yet found

the place outside laboratory but accidental

introduction of new organism in the outside

nature can be very dangerous. Just imagine

if synthetic virus as was created by Autodesk

will exchange genetic material with other

infectious agent. Therefore, it is important to

outline guidelines. At the same time we can’t

deny the fact that there is the need for new

source of energy, medicine, agricultural

products etc. and for this we need to invest in

synthetic life research.

Table 2 mentions the important

products which can be derived from research

on synthetic life. At research level,

challenges are to design the living system

from scratch. Understanding what sort of

ingredient in what proportion will be required

is yet to be explored in detail. Creating a lipid

based membrane which can carry several

molecules inside is still a very challenging

task. Recently researchers used the

microfluidics based approach for developing

lipid bubbles which is similar to living cell

membrane [12]. At last synthetic life research

should not be driven by profit but by future

need which cannot be solved by existing

resource.

References

1. Gibson DG, Glass JI, Lartigue C et. al.

Creation of a bacterial cell controlled by a

chemically synthesized genome.

Science. 2010 Jul 2;329 (5987):52-6. doi:

10.1126/science.

2. Slomovic S, Pardee K, Collins JJ et. al.

Synthetic biology devices for in vitro and

in vivo diagnostics. Proc Natl Acad Sci U

S A. 2015 Nov 24;112 (47):14429-35.

3. Paddon CJ, Keasling JD. Semi-synthetic

artemisinin: a model for the use of

synthetic biology in pharmaceutical

development. Nat Rev Microbiol. 2014

May;12 (5):355-67.

4. https://cosmosmagazine.com/biology/life-

2-0-inside-the-synthetic-biology-

revolution

5. Benenson Y. Biomolecular computing

systems: principles, progress and

potential. Nat Rev Genet. 2012 Jun 12;13

(7):455-68.

6. Roybal KT, Rupp LJ, Morsut L et. al.

Precision Tumor Recognition by T Cells


With Combinatorial Antigen-Sensing

Circuits. Cell. 2016 Feb 11;164 (4):770-9.

7. Wu MR, Jusiak B, Lu TK et. al. Engineering

advanced cancer therapies with synthetic

biology. Nat Rev Cancer. 2019 Apr;19

(4):187-195.

8.https://www.bbc.com/news/science-

environment-48297647

9. http://syntheticyeast.org/

10. Stano P. Is Research on "Synthetic Cells"

Moving to the Next Level? Life (Basel).

2018 Dec 26;9(1). pii: E3

11.https://www.vox.com/2014/5/5/11626456/

autodesk-builds-its-own-virus-as-the-

software-giant-develops-design

12. https://www.nature.com/articles/d41586-

018-07289-x


Neuroprostheses

By Megha Agrawal, PhD Executive Editor

Intra Spinal Micro-Stimulation Implant Technology Shows

Promise for Clinical Implementation

Intra Spinal Micro-Stimulation Implant for

Neuroprosthesis Recent breakthroughs in neuroprostheses

have accelerated a new wave of biomedical

technologies including implantable spinal-

cord-neuroprostheses that seek to restore

standing and walking after paralysis to

augment the human body or restore its lost

functions [1]. Researchers have extensively

studied these technologies in animal models

that have shown tremendous promise. One

of the therapeutic targets of these

neuroprostheses are neural networks of the

spinal cord that have been investigated for a

number of applications that include restoring

paralyzed limbs and mobility deficits, and

promoting targeted plasticity and recovery

after neural injury and disease [1-3]. Lately, the intra spinal micro-

stimulation (ISMS) implant has emerged as

an important procedure of neuroprostheses.

ISMS comprises of an array of ultra-fine

electrodes that are capable of delivering

electrical pulses to the ventral horns of the

spinal cord [4]. Researchers have shown that

depending on the targeted region within the

spinal cord, the application of ISMS can

generate functional movements of the lower

and upper limbs (lumbosacral and cervical

implants), breathing (cervical implant) or

bladder function (sacral implant) [1]. Further,

studies were conducted on stimulation

through an individual intraspinal electrode

that demonstrated the possibility to activate

motor networks including motoneurons,

afferent and propriospinal projections, and

associated axons spanning multiple spinal

cord segments. In further advances made in

ISMS, researchers showed that a small

number of implanted electrodes can evoke

synergistic muscle contractions, which can

produce coordinated movements involving

single or multiple joints to perform functional

tasks [1].

ISMS in the Lumbar Spinal Cord for

Overground Walking

The restoration of hind-limb movements after

paralysis is a very important medical

problem, and new biomedical solutions are

sought to address this issue. To this end,

ISMS in the lumbosacral spinal cord studied


in animals has shown great promise (Figure

1) [5].

Researchers showed that hind limb

movements triggered by ISMS in cats

resulted in significantly more fatigue resistant

compared to those obtained by intramuscular

electrical stimulation [3, 5]. It was

demonstrated that with ISMS implants,

animals were able to stand for ~5x longer

durations and walk over-ground for ~10x

longer distances than animals with

intramuscular implants [3].

Figure 1: Illustrations showing the experimental setup for over-ground walking. The process

involves sensor signals that come from force plates under the walkway and a gyroscope placed

on the tarsals from both hind-limbs. These signals are then converted to digital signals by the

data acquisition device (DAQ) and steamed into a Matlab program where an algorithm can

control the stimulation to the spinal cord to allow right-hind limb move to the opposite phase of

the walking cycle [Source: bioRxiv, (2019)].

Transitioning ISMS from Pre-Clinical

World to Clinical One

Transition of ISMS to full clinical

implementation is a critically important task

that requires understanding about the

functional organization of the motor networks

to be targeted in the lumbar spinal cord of

humans [1]. The existing information

regarding the anatomical organization of the

motoneuronal cell bodies in the human


lumbar spinal cord that innervate the leg

muscles (i.e., anatomical map) is not

sufficient to reveal the functional organization

and connectivity of various motoneuronal

pools (i.e., functional map). Further, the

required stimulation amplitudes for their

activation are also not known [1].

These steps are critical to design and

realize a clinical translation path of ISMS as

effective neuroprostheses. To this end,

researchers recently investigated the

organization of the neural networks targeted

by these implants in a non-human primate,

the macaque monkey. They presented the

hypotheses of their study based on

preservation of similar functional organization

of motor networks in non-human primates

(Figure 2) [1].

Figure 2: Experimental setup showing the concepts of functional mapping of the lumbosacral

spinal cord in non-human primates [Source: Scientific Reports, (2019)].

Concluding Remarks

Research advances made in spinal-cord

neuroprostheses have shown tremendous

promise for clinically improving lower limb

mobility after spinal cord injury (SCI). For

example, researchers have shown that by

targeting the motor networks in the ventral

horns of the spinal cord, ISMS can

specifically result in various coordinated leg

movements that are necessary for functional

tasks such as walking over-ground. In this

regard, preclinical studies have indicated the

potential of ISMS to produce beneficial

outcomes of standing and walking even after

a chronic complete SCI. Therefore, it is

believed that ISMS has the potential to

restore walking for people with more severe

SCIs than may be possible with any other

existing procedure such as epidural

stimulation. Further, to achieve the goal of

clinical implementation of ISMS implants, the


knowledge of the functional organization of

the motor inter-neuronal networks in the

lumbosacral spinal cord of humans is critical.

This involves the knowledge of exact location

of the spinal cord to place the implant for

successful targeting of the leg movements

that are required for functional standing and

walking. This will enable the optimized design

of the implant. Future technical design

considerations are expected to include the

number of microelectrodes in the array,

spacing between the microelectrodes, and

targeting depth and length of the

microelectrodes. We anticipate that further

R&D advances in specifications of the clinical

microelectrode and stimulator would pave the

way to safely deliver the current intensities

that are required for producing the pre-

requisite functional movements.

References

1. Amirali Toossi, Dirk G. Everaert, Steve I.

Perlmutter & Vivian K. Mushahwar,

Functional organization of motor

networks in the lumbosacral spinal cord

of non-human primates, Scientific

Reports, 9, Article number: 13539

(2019).

2. Mushahwar, V. K., Jacobs, P. L.,

Normann, R. A., Triolo, R. J. & Kleitman,

N. New functional electrical stimulation

approaches to standing and walking. J.

Neural Eng. 4, S181 (2007).

3. Tator, C. H., Minassian, K. & Mushahwar,

V. K. Spinal cord stimulation: therapeutic

benefits and movement generation after

spinal cord injury. Handb. Clin. Neurol.

109, 283–296 (2012).

4. Bamford, J. A., Lebel, R. M., Parseyan,

K. & Mushahwar, V. K. The fabrication,

implantation and stability of intraspinal

microwire arrays in the spinal cord of cat

and rat. Trans. Neural Syst. Rehabil.

Eng. (2016).

5. Ashley N Dalrymple, David A Roszko, Richard S Sutton, Vivian K Mushahwar, Pavlovian Control of Intraspinal Microstimulation to Produce Over-Ground Walking, bioRxiv, (2019), doi: https://doi.org/10.1101/785741.

https://www.nature.com/articles/s41598-019-49328-1#auth-1






Regenerative Medicine

By Shyamasri Biswas, PhD

Executive Editor

The Emerging Potentials of Exosome-Based Drug Delivery

Intercellular Communication through

Exosome Amplification: Reprogramming

of Cells

Exosomes are ultra-small (50-150 nm)

special membranous bio-vesicles. They are

released from living cells into surrounding

body fluids upon fusion of multi-vesicular

bodies (MVB) and the plasma membrane [1].

These extracellular vesicles are known to be

functional vehicles and carry cell-specific

cargos of proteins, lipids, nucleic acids and

genetic materials that can be selectively

taken up by neighboring or distant cells that

are located far from their release points.

Subsequently, the recipient cells are

reprogrammed through the triggered

bioactivities of exosomes [2].

Studies have indicated that the

bioactive molecules contained in exosomes

could impact target cells by direct stimulation

of target cells via surface-bound ligands and

transferring of activated receptors to recipient

cells. The subsequent epigenetic

reprogramming of recipient cells can happen

via the delivery of functional proteins, lipids,

and RNAs (Figure 1) [2]. As Figure 1

schematically illustrates, the exosome

amplification can potentially enable

communication of parental cells with specific

proximal or distant target cells [2]. In this way,

exosomes represent an intercellular

communication mode that can be

implemented in many cellular processes

including immune response, signal

transduction and antigen presentation [2].

The regulated formation of exosomes,

specific makeup of their cargo and cell-

targeting specificity show high potential of

exosomes for their use as next generation

non-invasive diagnostic biomarkers, as well

as therapeutic carriers [1, 2].

Therapeutic Ability of Exosomes

Exosomes’ therapeutic and clinical

application potentials have attracted a lot of

attention, lately. One area of application that

is being considered is cancer diagnosis and

therapy. Studies have suggested that tumor-

derived exosomes or TDEx regulate tumor

microenvironment and assist in distant

metastasis [1]. Researchers have shown the

possibility of employing molecular markers

on exosomes or TDEx that can be an

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377728/figure/Fig1/


effective method as liquid biopsy indicator for

cancer diagnosis and prognostic monitoring

[1, 3].

Exosomes are also known for their

ability to cross cytoplasmic membrane and

the blood/brain barrier. This ability of

exosomes can be leveraged for therapeutic

delivery of drug molecules. Therefore, a great

deal of current research has focused on

using the potential of exosomes being a drug

carrier due to exosomes’ natural material

transportation properties, intrinsic long-term

circulatory capability, and excellent

biocompatibility that are considered suitable

to deliver a variety of chemicals, proteins,

nucleic acids and gene therapeutic agents [1,

2]. To this end, the modified exosomes were

shown to treat pancreatic cancer by

delivering siRNA, and the CD47 protein on

the exosomes prevented them from being

phagocytosed by immune cells. This makes

the exosomes more efficient than synthetic

analogiliposomes. Researchers utilized the

targeting effect of exosomes, and leveraged

it to apply drugs such as adriamycin directly

to tumor cells that limited the toxicity to

normal cells [3].

Figure 1: The schematic illustration showing intercellular communication involved in exosome

mediated process. (1) Direct surface-bound ligands by the recipient cells. (2) Transfer of

activated receptors to recipient cells. (3) Epigenetic reprogramming of recipient cells [Source:

Cell Biosci. 2019].


Further, studies were conducted on the

cellular immunity, angiogenesis, and

regenerative effects in cell therapy mediated

by mesenchymal stem cells (MSCs) and

some other cells that were implemented by

the exosomes released from these cells [4,

5]. The emerging field of exosome therapy

has shown great application potential from

oncology to regenerative medicine [1].

Figure 2: Various methods that are employed for loading specific proteins, nucleic acids and

small molecular drugs into exosomes [Source: Theranostics (2019)].


Exosomes Loaded with Small Molecule

Drugs

Exosomes can be employed as carriers of

chemotherapy drugs. Researchers have

developed methods of loading small

molecule drugs into exosomes that include

direct mixing, incubation, ultrasonic

treatment, and eddy oscillation [1]. In addition

to these methods, several other different

ways of loading catalase into exosomes were

demonstrated ex-vivo such as incubation,

saponin permeabilization, freeze and thaw,

sonication, and extrusion that were employed

to treat Parkinson's disease. These methods

have been demonstrated for their use to load

exosomes with small molecule drugs as well.

The current state-of-the-art employs

most of these passive loading methods for

small molecule drugs that are loaded into

exosomes. However, major drawbacks of

these methods and approaches are the

resulting loss and degradation of exosomes

from multiple purification steps that are used

in these methods. Also, a prolonged in-vitro

treatment and the inherent physicochemical

properties of drug molecules can affect the

bioactivity and degrade the stability of

exosomes. In view of these shortcomings,

current research has focused on viable

alternative methods that would enable the

stability of exosomes.

Figure 1 summarizes the methods for

loading the specific treating molecules

(proteins, nucleic acids and small chemicals)

into exosomes [1].

Figure 3: A schematic presentation showing design strategies for therapeutic exosome targeting

(AA-PEG: aminoethylanisamide-polyethylene glycol; GPI: glycosylphos-phatidylinositol; RVG:

rabies virus glycoprotein; VSVG: vesicular stomatitis virus glycoprotein; A33Ab-US: the surface-

carboxyl superparamagnetic iron oxide nanoparticles coated with A33 antibody, to bind to A33-

positive exosomes; iRGD: an αⅤ integrin-specific internalizing peptide; PDGFR TM domain:

PDGFR transmembrane domain) [Source: Theranostics (2019)].


Future Design Strategies for Therapeutic

Exosome Targeting

Figure 3 shows a number of design strategies

that are currently being developed for loading

and targeting to realize the therapeutic

potential of exosomes [1]. In the application

of therapeutic exosomes, future designs will

focus on accurately targeting a specific type

of cells including tumor cells or a certain type

of tissue (e.g., brain tissue) as opposed to

broad distribution of exosomes to the liver,

kidney and spleen. In view of this,

researchers are focusing on to improving the

targeting of exosomes through the study of

exosome donor cells and the modification of

surface molecules on exosomes [1].

Concluding Remarks

Studies have shown that exosomes can play

a crucial role in both physiological and

pathological processes including the capacity

of exosomes to load a wide range of content

including lipids, RNAs, and proteins to signal

specific recipient cells or tissues. This makes

them a promising diagnostic biomarker and

therapeutic tool for treatment of cancers and

other complex pathologies and offer exciting

new possibilities in drug delivery. The early

studies indicate the great clinical potential

and value of exosomes due to their strong

biocompatibility, offering a new frontier in

drug delivery. We anticipate a rapid growth in

research and developments in the future

especially in the area of large scale

production of exosomes for clinical use.

References

1. Chunying Liu and Changqing Su, Design

strategies and application progress of

therapeutic exosomes, Theranostics.

2019; 9(4): 1015–1028.

2. Yuan Zhang, Yunfeng Liu, Haiying Liu,

and Wai Ho Tang, Exosomes: biogenesis,

biologic function and clinical potential,

Cell Biosci. 2019; 9: 19.

3. Kamerkar S, LeBleu VS, Sugimoto H,

Yang S, Ruivo CF, Melo SA. et al.

Exosomes facilitate therapeutic targeting

of oncogenic KRAS in pancreatic cancer.

Nature. 2017;546:498–503.

4. Baglio SR, Pegtel DM, Baldini N.

Mesenchymal stem cell secreted vesicles

provide novel opportunities in (stem) cell-

free therapy. Front Physiol. 2012;3:359.

5. Barile L, Lionetti V, Cervio E, Matteucci M,

Gherghiceanu M, Popescu LM. et al.

Extracellular vesicles from human cardiac

progenitor cells inhibit cardiomyocyte

apoptosis and improve cardiac function

after myocardial infarction. Cardiovasc

Res. 2014;103:530–41.


Biotechnology Advances around the World

Editor’s Picks

Every issue of Biotechnology Kiosk presents select latest research news picked by the executive

editors on significant research breakthroughs in different areas of biotechnology around the

world. The aim is to promote further R&D in all of these cutting edge areas of biotechnology. The

editors have compiled and included the following innovations and breakthroughs to highlight the

recent biotechnology advances.

Dr. Megha Agrawal Dr. Shyamasri Biswas

Executive Editor Executive Editor


Marine Biotechnology

Revealing the structure of the

microbial coated plastic marine

debris

The world's ocean is vulnerable to pollution

caused by millions of tons of tiny pieces of

dumped microplastics in the ocean. These

plastic marine debris (PMD) can be ingested

by even the smallest marine animals that can

potentially threaten their survival. It is

believed that PMD can seriously affect spatial

scales of life from microbes to whales. These marine microplastics or PMDs

upon entering the aquatic environment get

quickly coated with a layer of organic and

inorganic substances. Subsequently, a rapid

colonization of bacterial and eukaryotic

(micro) organisms happens that results in a

thin biofilm coating of bacteria and other

microbes, which is called the plastisphere.

While there have been studies on the impacts

of PMD on marine animals, the interactions

between PMD and microscopic life and

especially microbes are not sufficiently

explored. To address this issue, a

collaborative team of researchers in the US

and Netherlands used an innovative

microscopy method to reveal the structure of

the microbial communities coating

microplastic samples from a variety of ocean

sites. Their results were recently published in

Molecular Ecology Resources (Spatial

structure in the “Plastisphere”: Molecular

resources for imaging microscopic

communities on plastic marine debris,

Molecular Ecology Resources, 2019; DOI:

10.1111/1755-0998.13119).

This study involved a combinatorial

approach consisting of labelling and spectral

imaging based on fluorescence in-situ

hybridization (CLASI‐FISH), method and

using confocal microscopy to study

Plastisphere communities. Researchers

created a probe set that included three

existing phylogenetic probes (targeting all

Bacteria, Alpha‐, and Gammaproteobacteria)

and four specially designed probes (targeting

Bacteroidetes, Vibrionaceae,

Rhodobacteraceae and Alteromonadaceae).

These were then labelled with a total of seven

fluorophores and validated the probe set

using pure cultures.

Researchers envision that future

applications of this study could pave the way

to visualize specific groups of microbes to

investigate real-time their interactions with

the substrate surface. This includes possible

polymer hydrolysers that contribute to PMD

degradation.

Environmental Biotechnology

Reducing air pollution can have

dramatic health benefits

In the world today, poor air quality or ambient

air pollution including household air pollution

is a serious environmental risk to human

health that can affect almost every organ in

the body and result in morbidity and mortality.

In a comprehensive study, an international

team of bio and medical researchers from the

US, Mexico, UK, Germany, Korea and South

Africa looked at the health benefits of

pollution reduction at different levels of


interventions. They published their paper in

Annals of the American Thoracic Society

(Health Benefits of Air Pollution Reduction,

Annals of the American Thoracic Society,

2019; 16 (12): 1478 DOI:

10.1513/AnnalsATS.201907-538CME). In

their study, they investigated the impact of

reductions in air pollution on human health

that showed fast and dramatic impacts on

health-outcomes, as well as decreases in all-

cause morbidity. This important study

showed that reducing pollution at its source

can have a rapid and substantial impact on

health. For example, researchers

demonstrated that imposing a ban on

smoking for week yielded a 13 percent drop

in all-cause mortality, a 26 percent reduction

in ischemic heart disease, a 32 percent

reduction in stroke, and a 38 percent

reduction in chronic obstructive pulmonary

disease. Some of the significant health

benefits could be achieved within a few

weeks that included disappearance of

shortness of breath, cough, phlegm, and sore

throat. Other socio-health beneficial impacts

included reduction of school absenteeism,

clinic visits, hospitalizations, premature

births, cardiovascular illness and death.

Researchers showed that these

interventions are cost-effective and can be

implemented and reducing factors causing

air pollution and climate change can have

strong health benefits.

Virology

Breakthrough in solving structure

of key pneumonia virus enzyme

It is known that respiratory syncytial virus

(RSV) and human metapneumovirus (HMPV)

cause severe respiratory diseases in

humans. Past studies have shown that RSV

and HMPV are two interlinked viruses that

cause severe and life-threatening respiratory

diseases such as pneumonia and

bronchiolitis mostly in premature babies and

infants, and also these viruses affect the

elderly, and anyone with a weak immune

system. However, despite clinical advances,

there is no effective vaccine or an antiviral

therapy that exists to control or eliminate

RSV or HMPV infections.

HMPV and RSV control the cell's internal

mechanisms to make copies of themselves

when they infect human cells. Special

proteins are released by the virus that starts

the process of replication. Subsequently,

distinct protein complexes are created from

the interaction of these viruses with each

other.

In a new research, a team of molecular

and structural biologists in Singapore have

reported the structure of one of its key

components and proposed a potential new

route to disabling respiratory syncytial virus

(RSV) and human metapneumovirus

(HMPV). Their research was published in

Nature (Structure of the human

metapneumovirus polymerase

phosphoprotein complex, Nature, 2019; DOI:

10.1038/s41586-019-1759-1). Researchers

revealed the detailed structural knowledge

that can pave the way to develop inhibitors to

disrupt the enzymatic activities of HPMV L:P

protein and potentially block infection by the

virus. They envision their study would open

up new therapeutic pathways to help


researchers in pharma and academia to

design much needed therapies for treating

severe viral infections. It is hoped that

inhibitors developed against HPMV could

also work against a broad spectrum of

viruses involved in respiratory diseases.

Tropical Medicine

Genetic modification of malaria

carrying mosquitos

It is known that the transmission of malaria in

most of sub-Saharan Africa is carried out by

the primary mosquito vector Anopheles

gambiae. Past studies have shown that the

resistance in Anopheles gambiae

mosquitoes to members of all 4 major classes

(pyrethroids, carbamates, organochlorines,

and organophosphates) of public health

insecticides can seriously affect malaria

control programs.

Discovering the underlying molecular basis is

critical to overcome this issue. To this end,

studies have shown an increase in

expression of detoxifying enzymes

associated with insecticide resistance.

However, the knowledge about their direct

functional validation in An. gambiae is still not

adequate. It is therefore, believed that

understanding the mechanisms by which

mosquitoes evolve resistance is essential

that will enable the design and

implementation of mitigation strategies along

with the evaluation of new classes of

insecticides.

In a breakthrough in this area, researchers in

the UK recently published research results on

genetically modified malaria carrying

mosquitoes that demonstrated the role of

particular genes in conferring insecticide

resistance (Functional genetic validation of

key genes conferring insecticide resistance in

the major African malaria vector, Anopheles

gambiae, Proceedings of the National

Academy of Sciences, 2019; 201914633

DOI: 10.1073/pnas.1914633116).

Researchers showed for the first time

characterization of three genes (Cyp6m2,

Cyp6p3 and Gste2) associated with

insecticide resistance. This was

accomplished by their direct overproduction

in genetically modified Anopheles gambiae.

This significant breakthrough has revealed

that increased production of just these three

genes can cause the mosquitoes to become

resistant to all four classes of public health

insecticides that are currently being used in

malaria control. This study validate particular

genes as excellent markers for resistance

that can be employed as tools to monitor the

problem through molecular testing.

Alternative Medicine

Positive effects of drinking tea on

the brain structure

The main health benefits of tea come

primarily from its constituents including

catechin, L-theanine and caffeine. Among

these constituents, catechin has been

reported to be beneficial to cognitive health

that has shown enhancements in memory

recognition and memory performance in both

animal and human studies. In majority of

these studies, more focus has been given on

understanding neuropsychological measures


and studies on neuroimaging measures,

especially for interregional connections are

required to be done to better understand the

mechanisms of health benefits of tea as an

alternative form of medicine.

In a recent study, researchers in Singapore

and China revealed that regular tea drinkers

can have better organized brain regions.

They compared with non-tea drinkers and

reported noticeable health benefits

associated with healthy cognitive function

from drinking tea. This discovery was made

the researchers after examining

neuroimaging data of 36 older adults and

they published their research in Aging

(Habitual tea drinking modulates brain

efficiency: evidence from brain connectivity

evaluation, Aging, 2019; 11 (11): 3876 DOI:

10.18632/aging.102023)

The results of this study showed the first

evidence of positive contribution of tea

drinking to brain structure, and suggested

that drinking tea regularly could potentially

impart a protective effect against age-related

decline in the organization of brain structure.

This research shows the importance of

further work in this area as cognitive

performance and brain organization are

closely related. This would help better

understand how important cognitive functions

work such as emerging of memory from brain

circuits, and how the possible interventions

can take place to better preserve cognition

during the ageing process.

Compiled and Edited by Dr. Megha

Agrawal and Dr. Shyamasri Biswas.


Biotech and Pharma Industry Roundup

AstraZeneca and Daiichi Sankyo

present positive data of breast

cancer drug trastuzumab

deruxtecan

In a ray of hope for breast cancer patients,

AstraZeneca and Daiichi Sankyo presented

positive data of trastuzumab deruxtecan (DS-

8201) from their Phase II single-arm

DESTINY-Breast01 trial in HER2-positive

metastatic breast cancer patients. These

patients received two or more previous HER-

2 targeted regimens. The objective response

rate (ORR), was found to be 60.9% with the

drug alone [Source:

https://www.biospace.com/].

Merck’s inhibitor Keytruda

(pembrolizumab) shows promise in

the treatment of lung cancer

patients

Merck reported brand new findings at the

European Society for Medical Oncology

(ESMO) Immuno-Oncology Congress 2019

from its Phase III KEYNOTE-042 Study that

showed improvements in overall survival,

progression-free survival and overall

response rate in patients treated with

Keytruda as a monotherapy. The promising

findings of Keytruda showed the reported

benefits as a first-line treatment for patients

that were affected with metastatic

nonsquamous non-small cell lung cancer

(NSCLC) and whose tumors expressed PD-

L1 regardless of KRAS mutation. The data on

Keytruda demonstrated significant upward

benefits that included reduced risk of death

by 58% in patients with any KRAS mutation

and by 72% in patients with the KRAS G12C

mutation compared to chemotherapy

[Source: https://www.biospace.com/].

Alvogen to acquire the product

Gralise® (gabapentin) from

Assertio Therapeutics

Assertio Therapeutics, Inc., (“Assertio”) will

transfer all responsibilities associated with

the product Gralise® (gabapentin) to Alvogen

expectedly in January 2020, subject to

regulatory approval. This announcement was

made recently. To acquire the product,

Alvogen will pay Assertio a total value of

$127.5 million [Source:

https://www.biospace.com/].

Eleven biopharma companies filed

for bankruptcy (chapter 11) in 2019

Chapter 11 filings are considered rare in the

biotech and pharma industries. However, a

high number of drug makers including

Purdue Pharma, Achaogen and Pernix

Therapeutics filed for chapter 11 so far in this

year than in any year since at least 2011. The

reasons are legal liabilities that loomed large

with several drug makers that felt the weight

of thousands of opioids lawsuits. On the other

hand, prominent antibiotics makers


Achaogen and Aradigm struggled in 2019

due to apparent commercial roadblocks.

Despite the FDA approval, antimicrobial

drugs had apparently a market failure

according to industry experts [Source:

https://www.biopharmadive.com/).

Sanofi plans to stop diabetes, heart

research and $2.2B in cost cutting

going forward

Sanofi's new CEO, Paul Hudson plans to

shake up the French pharma giant in a recent

announcement. As a future plan, Sanofi will

stop all research in the disease areas

involving diabetes and cardiovascular

programs, and reduce costs by 2 billion

euros, or about $2.2 billion, by 2022. These

savings are expected to come from spending

less on expenses such as travel, consultants

and training costs, and reduced investments

in deprioritized businesses including diabetes

and cardiovascular, and manufacturing

improvements [Source:

https://www.biopharmadive.com/)].

The British pharma AstraZeneca is

growing

AstraZeneca showed a robust performance

in 2019. For example, its oncology business

led by its versatile products such as Tagrisso,

Imfinzi and Lynparza matched the sales of its

strong cholesterol-lowering statin pill Crestor

at its peak that came out to be more than $6

billion [Source:


Merck diversifies its cancer drug

pipeline through a $2.7 billion

acquisition of biotech firm ArQule

Merck & Co. recently announced its plans to

diversify its cancer drug pipeline through a

$2.7 billion acquisition of ArQule. [Source:


Madrid-based RNA specialist

Bioncotech Therapeutics enters

into a Phase II clinical trial

collaboration with a MSD subsidiary

The clinical collaboration between

Bioncotech Therapeutics and Merck Sharpe

& Dohme’s aims at providing clincial Phase II

evidence that’ RNA–based cancer lead BO-

112 can improve the efficacy of PD1

checkpoint inhibitor pembrolizumab in

partients with tadvanced-stage solid tumors

with liver metastases [Source:

https://european-biotechnology.com/].

Pierre Fabre to amend license

agreement with Puma

Biotechnology

In a recent announcement, Pierre Fabre SA

and Puma Biotechnology, Inc. have agreed

to broaden the geographic coverage of their

license agreement on commercialization of

Nerlynx® (neratinib). The amended and

extended agreement allows Pierre Fabre to

not only market the breast cancer recurrence

blocker Nerlynx® (neratinib) within Europe

and part of Africa but also in the Middle East

and several African territories [Source:

https://european-biotechnology.com/].


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